Aryl-carbaldehyde oxime derivatives and their use as estrogenic agents

Abstract

This invention provides estrogen receptor modulators having the structure where R 1 –R 5 are as defined in the specification; or a pharmaceutically acceptable salt thereof.

1. A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; 
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring; 
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; 
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and 
 R 6  is lower alkyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. The compound of  claim 1  where R 4  is hydrogen. 
     
     
       3. The compound of  claim 2  wherein R 1  is halogen. 
     
     
       4. The compound of  claim 2  wherein R 2  and R 3 , together, form a 5- or 6-membered ring. 
     
     
       5. The compound of  claim 2  wherein R 4  is hydrogen or halogen. 
     
     
       6. The compound of  claim 2  wherein:
 R 1  is halogen; 
 R 2  and R 3 , together, form a phenyl, furan, or thiophene ring; and 
 R 4  is hydrogen or halogen. 
 
     
     
       7. The compound of  claim 6  wherein R 1  is F and R 4  is hydrogen or F. 
     
     
       8. The compound of  claim 1  that is:
 (a) 4-(4-Hydroxyphenyl)-1-naphthaldehyde oxime; 
 (b) 4-(3-Fluoro-4-hydroxyphenyl)-naphthalene-1-carbaldehyde oxime; 
 (c) 4-(4-Hydroxyphenyl)-1-benzothiophene-7-carbaldehyde oxime; 
 (d) 7-(4-Hydroxyphenyl)-1-benzothiophene-4-carbaldehyde oxime; 
 (e) 7-(4-Hydroxyphenyl)-1-benzofuran-4-carbaldehyde oxime; 
 (f) 4-(4-Hydroxyphenyl)-benzofuran-7-carbaldehyde oxime; 
 (g) 5-(4-Hydroxyphenyl)-1-benzofuran-7-carbaldehyde oxime; or 
 (h) 7-(4-Hydroxyphenyl)-benzofuran-5-carbaldehyde oxime. 
 
     
     
       9. A pharmaceutical composition comprising:
 a compound of the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; 
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring; 
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; 
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and 
 R 6  is lower alkyl; 
 
       or a pharmaceutically acceptable salt thereof; and
 a pharmaceutically acceptable carrier. 
 
     
     
       10. A method of inhibiting osteoporosis in a mammal in need thereof, comprising providing to said mammal an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; 
 R 2  and R 3 , together, form a fused aryl or heteroaryl ring; 
 R 4  is hydrogen, halogen, lower alkyl, CN, or lower alkoxy; 
 R 5  is hydrogen, lower alkyl, or —C(O)R 6 ; and 
 R 6  is lower alkyl; 
 
       or a pharmaceutically acceptable salt thereof.